The present invention relates generally to phosphatidyl choline compounds useful as pharmaceuticals which are analogs of 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine, also known as platelet activating factor or PAF-acether.
Platelet activating factor (PAF-acether) is a potent mediator of anaphylaxis and inflammation. Among its physiological effects are activation of blood platelets and neutrophils and antihypertensive activity related to effects on smooth muscle cells.
Phospholipase A.sub.2 is a phospholipid-hydrolyzing enzyme which is involved in the physiological response to PAF-acether. Inhibitors of this enzyme are useful in regulating various aspects of phospholipid biochemistry in vivo.
Tence et al., Biochimie 63: 723 (1981), disclose fourteen structural analogs of PAF-acether which are tested for platelet aggregating activity. Although several of the compounds tested were active, none contained a sulfur at the C-1 position nor a nitrogen at the C-2 position of the glycerol. This reference suggests that an ether linkage at position C-1 of the sn-glycerol and a short acyl chain at position C-2 are required for activity.
Hadvary et al., Thrombosis Research 30: 143 (1983), disclose structures of 26 synthetic analogs of PAF-acether and the relative activities of the disclosed compounds in triggering aggregation of rabbit and human platelets. All analogs disclosed were characterized by an ether-alkyl linkage at the C-1 position. Of the compounds tested, only those having short chain ester moieties at the C-2 position were active. Replacement at the C-2 position by formyl as well as by the butyryl esters significantly degraded activity.
Chandrakumar et al., Tetrahedron Letters 22: 2949 (1981), disclose use of serine in a synthetic method for making analogs of PAF-acether. The disclosed method yielded compounds of desired chirality for possible use as phospholipase inhibitors. Synthesis of 1-O-acetoalkyl-2-palmitoylamido-2-deoxy-3-O-phosphorylcholine is disclosed. No results of biological testing are provided.
Betzing et al., European Published Patent Application No. 43,472 (1981), disclose analogs of PAF-acether having a thioether linkage at position C-1 of the glycerolphosphorylcholine nucleus. These compounds exhibited anti-hypertensive activity.